Regulation of the immune response to the muscle stage of the parasitic nematode Trichinella spiralis
The parasitic nematode Trichinella spiralis is a natural pathogen of rodents and humans, exhibits a broad host and geographic range, and has served as a valuable model for the study of mucosal immunity. Little is known, however, of the cellular immune response to the chronic and disseminated stage of the parasite that resides within individual, striated skeletal muscle cells. Despite a potent humoral response to muscle stage parasites, there is limited cellular infiltration of infected muscle. We hypothesized that suppression of inflammation was an active process mediated by T helper type 2 (TH2) responses that are characteristic of helminth infections. To address this hypothesis we conducted in vivo experiments using a synchronous model of infection that bypassed the intestine and allowed us to examine the immune response specifically to muscle-stage parasites. We utilized transgenic mice, adoptive transfer of specific cell populations, flow cytometry, cytokine analysis, histology and immunohistochemistry to characterize the cellular infiltrate that is recruited to infected muscle, identify molecules that modulate this inflammatory response, and finally, to delineate the mechanisms of effector T cell suppression during infection. The results presented here show that the inflammatory response to muscle larvae is rich in macrophages and CD4 T cells, peaks in intensity at the completion of parasite maturation, and is rapidly down modulated coincident with a shift to T helper type 2 (TH2)-driven response. Our studies in interleukin-10 deficient mice revealed a critical role for this cytokine in controlling inflammation during parasite development, but showed that it is not required during chronic infection. In the absence of IL-10, antigen-specific interferon-? (IFN-?) production and local synthesis of inducible nitric oxide synthase (iNOS) increased dramatically, while TH2 cytokines were unaffected. Our adoptive transfer studies showed that effector T cells were the critical source of IL-10 and are sufficient to protect mice from myositis. In contrast, we found that naturally-occurring regulatory T cells inhibit TH2 responses but do not influence local inflammation. Finally, we provide evidence that, in the absence of IL-10, the pluripotent cytokine transforming growth factor-? (TGF-?) is critical in limiting myositis and protecting parasites in the muscle.
Immunity; Nematode; Interleukin-10; inflammation; Trichinella spiralis; transgenic
dissertation or thesis